Chris A. Johnson - US grants

This project will provide a comprehensive investigation of automated perimetry. A combination of clinical, psychophysical and theoretical approaches will be employed to accomplish the following objectives: (1) Provide test protocols, guidelines and recommended standards for automated priemetry (applicable to all commercially-available automated visual field devices) for the general practitioner to use for screening, differential diagnosis and quantitative assessment of the visual field. (2) Provide a thorough comparison of different test parameters, strategies and stimulus conditions associated with automated perimetry to define the capabilities, limitations and performance characteristics of different approaches to automated perimetry. (3) Develop heuristic, interactive strategies for automated perimetry to make the procedures more efficient and appropriate for clinical foundation for various forms of automated visual field testing. (5) Develop population distribution characteristics and quantitative models of normal visual fields for different age groups, and abnormal visual fields for specific eye diseases. Computer simulation techniques, probabalistic and statistical evaluation procedures, and clinical testing of selected patient populations will all be employed to achieve the objectives described above.

This project will provide a comprehensive investigation of automated perimetry. A combination of clinical, psychophysical and theoretical approaches will be employed to accomplish the following objectives: (1) Provide test protocols, guidelines and recommended standards for automated priemetry (applicable to all commercially-available automated visual field devices) for the general practitioner to use for screening, differential diagnosis and quantitative assessment of the visual field. (2) Provide a thorough comparison of different test parameters, strategies and stimulus conditions associated with automated perimetry to define the capabilities, limitations and performance characteristics of different approaches to automated perimetry. (3) Develop heuristic, interactive strategies for automated perimetry to make the procedures more efficient and appropriate for clinical foundation for various forms of automated visual field testing. (5) Develop population distribution characteristics and quantitative models of normal visual fields for different age groups, and abnormal visual fields for specific eye diseases. Computer simulation techniques, probabalistic and statistical evaluation procedures, and clinical testing of selected patient populations will all be employed to achieve the objectives described above.

Optic neuritis is a common optic nerve disorder usually affecting individuals between the ages of 15 and 45. The pathogenesis is related to demyelination regardless of whether or not multiple sclerosis is present. Because there were no established guidelines to follow in deciding upon a treatment for a patient with this condition, the Optic Neuritis Treatment Trial (ONTT) was initiated. The ONTT protocol was designed to determine the value of corticosteroids in the treatment of optic neuritis. Two primary outcome measures, contrast sensitivity and visual field sensitivity, and two secondary outcome measures, color discrimination and visual acuity, were utilized to assess treatment efficacy. The major objective of this research project is to conduct a detailed analysis of visual field data from the ONTT. Although visual field information was used as an outcome measure in the ONTT study, only general summary values were examined. This project will incorporate a thorough evaluation of visual field data from the ONTT that is directed to four primary issues: (1) Determine the relationship of specific patterns of visual field loss to final visual outcome, recurrences of visual loss and treatment. (2) Quantitatively characterize the loss and recovery of visual field sensitivity in optic neuritis. (3) Evaluate the interrelationships among patient response characteristics, test conditions and visual field results. (4) Compare existing visual field analysis procedures and develop new methods of quantitatively evaluating and characterizing visual field loss. The visual field database for the ONTT provides a unique opportunity to evaluate visual field loss in optic neuritis. The use of stringent test protocols, the standardization of equipment and test procedures, the training and certification of visual field technicians, the quality control assessment of all visual field examinations, the high compliance of patients in meeting their scheduled appointments, and the automated data conversion and processing procedures all ensure that the ONTT visual field database is of higher quality than any previous multi-center study. These factors, in conjunction with the size of the patient population, the large number of. visual field examinations per patient, and the high compliance for scheduled followup visits make it possible to conduct a detailed examination of visual field properties in optic neuritis, determine the prognostic value of specific visual field characteristics, and evaluate the possibility of additional differences in visual field properties among treatment groups. In addition, the variety of visual field deficits that are present in optic neuritis makes the ONTT database an ideal resource for developing and evaluating different quantitative visual field analysis procedures.

The Ocular Hypertension Treatment Study (OHTS) is a long-term randomized multicenter clinical trial that began in 1994 to determine whether medical reduction of intraocular pressure prevents or delays the onset of glaucomatous optic nerve damage and/or visual field loss in ocular hypertensive subjects. More than 1,500 subjects with intraocular pressures of greater than or equal to 24 mm Hg but less than or equal to 32 mm Hg in at least one eye (with an intraocular pressure of 21 mm Hg or greater in the fellow eye), and normal visual fields and normal optic discs in both eyes were randomly assigned to receive stepped medical treatment to both eyes or to close observation only to both eyes. Participants have been followed for approximately five years with conventional automated perimetry twice yearly and stereoscopic optic disc photographs once yearly. The study endpoints are reproducible optic nerve damage and/or reproducible glaucomatous visual field loss in either eye of a patient. Short Wavelength Automated Perimetry (SWAP) is a new visual field test procedure that isolates and measures the sensitivity of short wavelength (blue) sensitive visual mechanisms by projecting large (Size V) blue targets on a high luminance yellow background. Previous longitudinal studies conducted at the University of California, Davis and the University of California, San Diego have established that (1) SWAP is more sensitive than conventional automated perimetry for detection of early losses in glaucoma, (2) SWAP deficits in ocular hypertensive patients and glaucoma suspects are predictive of the onset and location of future glaucomatous visual field loss for standard automated perimetry, (3) that the progression of SWAP deficits is approximately twice as great as for standard automated perimetry, and (4) that early SWAP deficits is ocular hypertensive patients and glaucoma suspects are correlated with other risk factors associated with the development of glaucoma, especially glaucomatous optic disc cupping. This proposal requests a 5 year extension of the original SWAP ancillary study to the OHTS trial. Since 1994, more than 350 OHTS patients have been enrolled in the SWAP ancillary study. The main objective of this study is to determine the effect of treatment versus no treatment on SWAP results in ocular hypertensive patients. In particular, this investigation will examine the influence of treatment on reversibility of early SWAP deficits, determine whether progression of SWAP deficits is retarded by treatment, and whether the incidence of new SWAP deficits during the OHTS trial are reduced by treatment. A secondary goal of this study is to confirm previous findings that SWAP can predict the onset and location of future glaucomatous visual field loss, and that progression of SWAP deficits is more than twice as rapid as progression of visual field loss with conventional automated perimetry. Additionally, the prevalence of SWAP deficits in African American patients participating in OHTS will be evaluated to determine whether African-American ocular hypertensives have a higher prevalence of SWAP deficits.

DESCRIPTION (Provided by applicant): Glaucoma is a disease characterized by optic nerve damage (retinal ganglion cell loss), and is one of the leading causes of blindness. It is estimated that 2 million people in the United States have been diagnosed with glaucoma, 1 million others have undiagnosed glaucoma, and up to 6 million (including 4-8 percent of people over 40) are at risk of developing glaucoma. Our current understanding of early damage in glaucoma, however, remains limited. Histopathologic studies in humans and experimental primate glaucoma models suggest that there can be substantial loss of retinal ganglion cells before reliable changes in visual function can be measured. This project will investigate a new method of noninvasively monitoring retinal ganglion cell loss, and potential functional and structural predictors of this loss. Our first aim determines the effect of glaucomatous retinal ganglion cell loss on cortical responses. Most new visual function tests for glaucoma have attempted to isolate and measure response properties of retinal ganglion cell subpopulations. We will use a noninvasive electrophysiology procedure, the multifocal Visual Evoked Potential (mfVEP), to measure cortical responses and the consequences of retinal ganglion cell loss on these responses. Because cortical responses are dependent on summed ganglion cell input, we propose that the mfVEP may be a more sensitive indicator of visual function loss, and may correlate more strongly with early structural optic nerve damage than other visual function measures. However, it is possible that retinal ganglion cell malfunction (sick cells) precedes the ganglion cell dropout (dead cells) investigated as part of our first aim. Our second aim therefore examines a method of functionally distinguishing sick from dead ganglion cells. We hypothesize that sick ganglion cells will show normal flicker sensitivity at lower adaptation levels, but will show deficits when challenged with higher adaptation levels. We will test the hypothesis that flicker adaptation dysfunction will predict future visual field deficits produced by retinal ganglion cell loss. In addition to these functional predictors of ganglion cell loss, our third aim evaluates the importance of structural damage to the optic nerve head (using stereo optic disc photographs and measurements with Heidelberg Retinal Tomography images) for predicting the location of future visual function deficits indicative of ganglion cell loss. Together, these objectives will provide a better understanding of the underlying basis of early glaucomatous damage.